Gene Transfer of Constitutively Active Akt Markedly Improves Human Islet Transplant Outcomes in Diabetic Severe Combined Immunodeficient Mice

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FIG. 4.FIG. 4.
FIG. 4.

A: Blood glucose levels in STZ-induced diabetic SCID mice after renal subcapsular transplant of uninfected, Adv-LacZ–and Adv-CA-Akt–transduced human islets. Twenty-four hours after transduction, 4,000 and 1,500 uninfected or 1,500 Adv-LacZ–or 1,500 Adv-CA-Akt–transduced human IEQs were transplanted under the kidney capsule of STZ-induced diabetic SCID mice. Results are means ± SE of six mice transplanted with six different human islet preparations per condition. In the group of mice transplanted with 1,500 Adv-LacZ IEQs (n = 5) one hyperglycemic transplanted mouse died at 28 days after the transplant. The posttransplant blood glucoses in mice transplanted with 1,500 Adv-CA-Akt–transduced IEQs or 4,000 uninfected IEQs were significantly lower (P < 0.05) than the blood glucose values obtained after the transplant of either 1,500 uninfected or 1,500 Adv-LacZ–transduced human IEQs. At day 56, unilateral nephrectomy (UNX) was performed in three mice transplanted with Adv-CA-Akt–transduced islets, and the blood glucose returned immediately to pretransplant diabetic levels. Blood glucose was measured in the other three mice transplanted with Adv-CA-Akt–transduced islets for up to 6 months (see Fig. 5). B: IPGTT in normal nondiabetic SCID mice and in STZ-induced diabetic mice transplanted with 1,500 Adv-LacZ- or 1,500 Adv-CA-Akt–transduced islets. At day 49 after the transplant, mice were fasted for 16 h and then injected with 2 g/kg body wt glucose. Blood glucose was measured from the snipped tail at the points indicated with a portable glucometer. Results are means ± SE. Blood glucose values were significantly lower (P < 0.05) in mice transplanted with Adv-CA-Akt–transduced islets compared with mice transplanted with Adv-LacZ–transduced islets. In fact, blood glucose values in mice transplanted with Adv-CA-Akt–transduced islets were similar to those of normal, nondiabetic SCID mice. C–H: Immunohistochemical detection of insulin- and CK-19–positive cells in kidney sections containing islet grafts from mice transplanted with 4,000 uninfected (C, E, and G) or 1,500 Adv-CA-Akt–transduced (D, F, and H) IEQs. Notice the presence of insulin-positive cells within ductal structures in the grafts (arrows in G and H).

This Article

  1. Diabetes vol. 54 no. 6 1664-1675